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Elucidating the functional role of KLRG1+ conventional helper T cells in the tumor microenvironment

Award Number: F32CA294616
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2025
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Elucidating the functional role of KLRG1+ conventional helper T cells in the tumor microenvironment - PROJECT SUMMARY/ABSTRACT The overall goal of this project is to define the functional role of killer cell lectin-like receptor G1 (KLRG1) expressing tumor-infiltrating CD4+ FoxP3- T conventional helper cells (Tconv) in cancer and to develop a novel immunotherapy to selectively deplete KLRG1-expressing CD4+ T cells for immunotherapy. Most clinically relevant immunotherapies aim to augment or de-repress CD8+ T cell cytotoxicity, despite the central role of CD4+ T cells in shaping antitumor immunity by altering the balance of inflammation and immunosuppression in the tumor microenvironment (TME). We have shown that KLRG1-expressing CD4+ T cell subsets, both Tconv and regulatory T cells (Tregs), are highly correlated with the rate of immune escape in murine and human tumors. Furthermore, these subsets are greatly reduced in tumors responding to immune checkpoint blockade (ICB), suggesting that KLRG1-expressing CD4+ T cells may be biomarkers of ICB response. In preliminary experiments, KLRG1+ Tconv cells express a highly distinct cytokine profile from their KLRG1- Tconv counterparts that closely resembles that of tumor Tregs. Additionally, initial experiments demonstrate that KLRG1+ Tconv cells are functionally immunosuppressive ex vivo, suggesting that this is a novel immunosuppressive cell type in the TME. KLRG1 is a co-inhibitory receptor that has a canonical negative regulatory role on NK cells and cytotoxic CD8+ T cells. However, the role of KLRG1 on CD4+ Tconv cells is essentially unknown. Thus, the first aim of this project will investigate the functional mechanisms by which KLRG1+ Tconv cells modify the TME. We will test the hypothesis that KLRG1+ Tconv cells are immunosuppressive through adoptive transfer experiments, secretome, transcriptome, and epigenetic profiling, and genetic depletion to establish the sufficiency and necessity of KLRG1 on Tconv cells to enhance tumor progression and immune escape. In the second aim, we will develop KLRG1-specific depleting monoclonal antibodies (mAbs) using glycoengineering strategies to compare depleting versus blocking immunotherapy in combination with standard anti-PD1 immunotherapy. We will also utilize a novel bispecific mAb to specifically deplete KLRG1-expressing CD4+ T cells and perform high parameter spectral flow cytometry to assess compositional shifts of tumor-infiltrating immune populations resulting from our novel immunotherapeutic strategy. Altogether, the proposed studies offer a hypothesis-driven approach to elucidate the functional mechanisms of KLRG1 on Tconv cells in the TME, while developing a novel therapeutic to deplete KLRG1-expressing CD4+ T cells as a novel cancer immunotherapy strategy.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $78,040 )
2025	2025	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Cancer Research Manpower	000	1	6/25/2025	NEW	$78,040
2025	2025	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Cancer Research Manpower	001	1	6/25/2025	NEW	$0
														Subtotal = $78,040

Grand Total All Awards = $78,040

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Elucidating the functional role of KLRG1+ conventional helper T cells in the tumor microenvironment

Award Number: F32CA294616

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2025

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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